Project Summary: Project 1 Although Parkinson disease (PD) is conventionally thought to be a condition primarily affecting the brain, recent studies have begun to shed light on the complex interactions between the brain and body involved in the disease, particularly the immune system. Innate immunity is mediated by cells of myeloid lineage: monocytes derived from bone marrow, tissue macrophages which arise from monocyte infiltration and differentiation, and the resident microglia of the brain which are independently derived from the embryonic yolk sac. Based on our preliminary data from the P20 Exploratory Grant Program, in this project our overarching hypothesis is that innate immune cells are activated towards a pro-inflammatory phenotype early in PD. We theorize that blocking this activation will protect from PD progression There are critical gaps in rigor of the available data which hinder the design and execution of future therapeutic trials of immunomodulation. These gaps include: 1) nearly all previous studies of inflammatory markers in PD have included heterogeneous groups of patients with a broad range of disease severity, durations and treatments; 2) there has been a lack of attention to sex as a biological variable; 3) there are no previous studies which directly examine monocytes populations in early PD, which we postulate to be critically important; 4) there is little information on longitudinal change in inflammatory markers; and 5) there is little data connecting brain and blood inflammatory markers to outcomes. Through the P20 program, we have established the ability to study a unique human subject cohort of early, de novo PD (a term meaning patients who have not yet received any anti-PD drug therapy) which will allow us to address these critical issues. Here we propose three aims which will directly address these critical knowledge gaps. In Aim 1, we will study a cohort of 60 patients with de novo PD and 60 age- and sex-matched controls recruited by the clinical core. We will determine whether peripheral immune activation or differentiation is associated with CNS inflammation in early PD through integrated analysis of blood monocytes, blood and CSF cytokines and chemokines, and brain imaging with the TSPO ligand 18F-DPA-714. In Aim 2, we will determine whether there is change over time in monocytes populations assessed by flow cytometry or in blood cytokines and chemokines. In Aim 3, we will examine the relationship between baseline measures of inflammation and longitudinal clinical outcomes, particularly cognition, in this population of early de novo PD subjects These Aims are closely integrated with other components of the Alabama Udall Center. All of the human data and biospecimens are drawn from the Clinical Research Core and will be studied in Project 2 (Benveniste, focused on JAK/STAT signaling) and Project 3 (West, focused on LRRK2). Together, these studies should provide a comprehensive view of the role of immune cells in PD, and identify targets for therapy.